Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (Affymetrix)

Small cell lung cancer (SCLC) is an aggressive disease with high mortality. The identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library we observe that SCLC is sensitive to transcription-targeting drugs, and in particular to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7). We find that expression of super-enhancer associated transcription factor genes including MYC family proto-oncogenes and neuroendocrine lineage-specific factors are highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a novel treatment paradigm for targeted SCLC therapy. Microarray expression in small cell lung cancer lines treated with DMSO or THZ1

小细胞肺癌（small cell lung cancer, SCLC）是一种侵袭性强、致死率高的恶性疾病。靶向SCLC生物学特性的有效药理策略研发，是当前亟待满足的临床需求。本研究通过对多样化化学文库开展高通量细胞筛选，发现SCLC对靶向转录的药物具有敏感性，尤其对新型共价细胞周期蛋白依赖性激酶7（cyclin-dependent kinase 7, CDK7）抑制剂THZ1敏感。我们发现，包括MYC家族原癌基因及神经内分泌谱系特异性因子在内的超级增强子相关转录因子基因的表达，对THZ1处理具有高度易感性。我们提出，这些转录因子的下调一定程度上促成了SCLC对转录抑制剂的敏感性，而THZ1则为SCLC的靶向治疗提供了全新的治疗范式。经二甲基亚砜（dimethyl sulfoxide, DMSO）或THZ1处理的小细胞肺癌细胞系的微阵列表达谱